siRNA 种子区域在响应 2'-OMe 修饰的 RNA 干扰中分为两个功能不同的域,ACS Omega

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siRNA 种子区域在响应 2'-OMe 修饰的 RNA 干扰中分为两个功能不同的域
ACS Omega ( IF 3.7 ) Pub Date : 2022-01-04 , DOI: 10.1021/acsomega.1c06455
Yoshiaki Kobayashi ₁ , Daiki Fukuhara ₂ , Dai Akase ₂ , Misako Aida ₂ , Kumiko Ui-Tei _{1,

3}

Affiliation

在 RNA 干扰 (RNAi) 中，小干扰 RNA (siRNA) 以完美的序列互补性抑制其靶 mRNA 的表达。在与上述不同的机制中，siRNA 还抑制具有部分序列互补性的非预期 mRNA，主要是 siRNA 种子区域（核苷酸 2-8）。这种机制主要被 microRNA (miRNA) 使用，并导致 siRNA 介导的脱靶效应。因此，认为 siRNA 种子区域涉及 RNAi 和脱靶效应。在这项研究中，我们揭示了 2'- O的影响-甲基（2'-OMe）修饰根据核苷酸位置而不同。核苷酸 2-5 的 2'-OMe 修饰抑制了脱靶效应，而不影响靶向 RNAi 活性。相反，核苷酸 6-8 的 2'-OMe 修饰增加了 RNAi 和脱靶活性。计算模拟显示，由 2'-OMe 修饰引起的结构变化在核苷酸 2-5 处中断了 siRNA 和靶/脱靶 mRNA 之间的碱基配对，但在核苷酸 6-8 处增强。因此，我们的结果表明，siRNA 种子区域由两个功能不同的结构域组成，以响应 2'-OMe 修饰：核苷酸 2-5 是避免脱靶效应所必需的，核苷酸 6-8 参与增强两种 RNAi和脱靶活动。

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siRNA Seed Region Is Divided into Two Functionally Different Domains in RNA Interference in Response to 2′-OMe Modifications

In RNA interference (RNAi), small interfering RNA (siRNA) functions to suppress the expression of its target mRNA with perfect sequence complementarity. In a mechanism different from above, siRNA also suppresses unintended mRNAs with partial sequence complementarities, mainly to the siRNA seed region (nucleotides 2–8). This mechanism is largely utilized by microRNAs (miRNAs) and results in siRNA-mediated off-target effects. Thus, the siRNA seed region is considered to be involved in both RNAi and off-target effects. In this study, we revealed that the impact of 2′-O-methyl (2′-OMe) modification is different according to the nucleotide positions. The 2′-OMe modifications of nucleotides 2–5 inhibited off-target effects without affecting on-target RNAi activities. In contrast, 2′-OMe modifications of nucleotides 6–8 increased both RNAi and off-target activities. The computational simulation revealed that the structural change induced by 2′-OMe modifications interrupts base pairing between siRNA and target/off-target mRNAs at nucleotides 2–5 but enhances at nucleotides 6–8. Thus, our results suggest that siRNA seed region consists of two functionally different domains in response to 2′-OMe modifications: nucleotides 2–5 are essential for avoiding off-target effects, and nucleotides 6–8 are involved in the enhancement of both RNAi and off-target activities.

更新日期：2022-01-18

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